It is well known that androgen deprivation is the cornerstone of initial therapy for metastatic prostate cancer. Once metastatic prostate cancer progresses in the face of hormonal therapy, it is classified as being androgen independent. Therapeutic options for patients with androgen independent prostate cancer are extremely limited. In particular, cytotoxic chemotherapy has provided minimal benefit. The purpose of this project is to perform translational research to develop new agents, and/or therapeutic maneuvers, that appear to have antitumor activity in prostate cancer. To achieve this goal, we have become extensively involved in the efforts to understand the biology of prostate cancer. Currently, we are attempting to correlate biological variables associated with prostate cancer and response to therapy (e.g., mutated androgen receptor, CAG repeats and microvessel count). The Molecular Pharmacology Sectionreported the first confirmation of the therapeutic efficacy of flutamide withdrawal, as well as the enhanced activity of simultaneous adrenal suppression. It has been hypothesized that the clinical improvement associated with flutamide is a result of the presence of a mutation within the ligand-binding domain of the androgen receptor. As we and others have reported, the human prostate cancer cell line LNCaP, which expresses such a mutated receptor, is stimulated to grow by hydroxy-flutamide, the active metabolite of flutamide. We believe that the mutation in the ligand-binding domain of the androgen receptor causes these normally antagonistic compounds to behave as androgen agonists. Whether this phenomenon is unique to the LNCaP cell line or is also responsible for the observations made in vivo is unknown. This question is being actively pursued in our section. More recently, we have initiated experiments in an attempt to determine which genes are regulated by the androgen receptor. In particular, we are interested in a polymorphism in the AR (a trinucleotide repeat in exon 1 -- CAG repeat). We are interested in analyzing several candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. All of the genes listed below have shown preliminary evidence that suggests that they may play important roles. Genes involved in the natural production of endostatin (COL18A1), the enzymes involved in testosterone processing (SRD5A1&2), drug metabolism (CYP3A4 &5), and genes involved in cellular transport and conjugation (UGT1A1, UGT2B15, UGT2B17) are being investigated for their involvement in the onset, progression and metastasis of prostate cancer.Some of the overall goals of this project are: (a) to better understand associations between important androgen regulatory gene polymorphisms and prostate cancer risk and (b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for prostate cancer. The recently completed Prostate Cancer Prevention Trial (PCPT) investigated the prevention of prostate cancer using the steroid 5 alpha-reductase inhibitor finasteride over a seven year treatment period. Through a longstanding collaboration we have access to tissue samples of the 18,800 men enrolled in this study. It has been proposed that polymorphisms within key regulatory genes may play a role in the susceptibility of an individual to the development of prostate cancer. We are currently focusing on hormone-related factors that are associated with prostate cancer risk, which may help explain the findings of the PCPT (i.e., decreased overall occurrence of adenocarcinoma, but increased prevalence of high-grade disease in the finasteride treatment arm). We hypothesize that men with polymorphisms within genes that positively impact androgen levels will have a higher risk of developing prostate cancer and high grade disease than those with the wild-type alleles. In addition, long-term exposure to finasteride may select for somatic alterations and increase serum levels of testosterone and potentially harmful testosterone breakdown products. We are evaluating whether polymorphic variations in the AR, CYP11a, CYP17, CYP1B1, and HSD3B2 genes are associated with the risk of biopsy-detected prostate cancer and whether the selected genotypes alter the effects of finasteride on prostate cancer occurrence. We are identifying somatic alterations in the AR and HSD3B2 that may have been selected for by long-term exposure to finasteride. Furthermore, we are determining whether prostate cancer somatic mutations of these genes differ with regard to their prevalence between the placebo and finasteride arms, and among PIA, HGPIN, prostate cancer and normal epithelium. These findings will help define a pharmacogenomic profile to identify men that are most likely to benefit from treatment with 5 alpha-reductase inhibitors.